Virologic failure detected in a quarter of ART-treated children in Tanzania

A quarter of children and adolescents in Tanzania taking antiretroviral therapy (ART) have major resistance to one or more anti-HIV drug, investigators report in AIDS.

In 86% of patients, resistance was acquired during therapy and significant risk factors for acquired resistance included therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI). Use of World Health Organization (WHO) criteria for immunological failure of treatment – which triggers a change in therapy – would have detected only 4% of cases of virological failure.

“To our knowledge, this is one of the first studies to comprehensively assess virologic failure and the acquisition of HIV-DRM [drug resistance-associated mutations] among a large paediatric population in Sub-Saharan Africa,” comment the investigators. “Key findings are a high rate of both virologic failure and acquired HIV-DRM after a median of over 4 years of ART and an increased risk of both virologic failure and HIV-DRM among participants receiving NNRTI, those with younger age at ART initiation and female patients.”

In 2015, an estimated 1.8 million children were living with HIV worldwide, the vast majority in sub-Saharan Africa. Only 49% of children in need of ART are receiving this treatment.

There are limited data on the long-term virologic effectiveness of ART in children and adolescents in resource-limited settings, where access to viral load monitoring is limited. An international team of investigators therefore designed a prospective cohort study involving 213 ART-treated children and adolescents who received care in rural Uganda. Their aims were to determine the prevalence of virologic failure (a viral load above 1000 copies/ml after 12 months of treatment), the prevalence of major resistance-associated mutations and the risk factors for virologic failure.

Eligible participants had been receiving ART for a minimum of one year (median, 4.3 years) and were aged under 18 years (median, 11 years). The majority (55%) had symptomatic HIV disease (WHO stages 3 and 4. The most commonly used first-line regimen was zidovudine/lamivudine/NNRTI (55%). At the time of analysis, 85% of participants were taking NNRT-based therapy. Good adherence (no missed doses in the previous four weeks) was recorded in 85% of individuals, but a quarter had changed their regimen at some point because of drug shortages or stock-outs.

At the time of analysis, 25% of participants had a viral load of 1000 copies/ml or above, thus meeting the WHO definition for virologic failure. Median viral load in these people was 20,615 copies/ml. An additional 18% of individuals had a detectable viral load of less than 1000 copies/ml.

Median CD4 percentage rose from 12% at ART initiation to 26% after 12 months of therapy, reaching a maximum of 31% after 60-65 months on ART. Immune recovery tended to be weaker among individuals with virologic failure, reaching 22% after 12 months compared to 27% for those without virologic failure.

Predictors of virologic failure were NNRTI-based ART (aOR = 7.32; 95% CI, 1.51-35.46, p = 0.013), sub-optimal adherence (aOR = 3.90; 95% CI, 1.11-13.68, p = 0.034) and female sex (aOR = 2.57; 95% CI, 1.03-6.45, p = 0.04). A higher CD4 percentage and older age were both protective against virologic failure.

Of the participants with virologic failure, 90% had at least one major resistance mutation; resistance to an NRTI was found in 81% of these individuals, with 90% having resistance to an NNRTI.

Analysis of pre-ART blood samples from 44 people with a major mutation showed that 85% had acquired a key resistance mutation during therapy, the remaining 15% having transmitted resistance.

Risk factors for acquired resistance were NNRTI-based therapy (aOR = 10.73; 95% CI, 1.75-65.70, p = 0.01) and female sex (aOR = 3.99; 95% CI, 1.40-11.41, p = 0.01). There was a non-significant association between poor adherence and acquired resistance. Higher CD4 percentage and older age were protective against this outcome.

Current WHO criteria for immunological treatment failure in children are a CD4 count below 200 cells/mm³ or 10% in the under-5s, and a CD4 count below 100 cells/mm³ for children aged 5-15 years. Only 3.7% of major resistance identified in the present study would have been picked up using WHO immunological failure criteria.

“Our study found high rates of virologic failure and emerging HIV-DRM in this paediatric population on long-term ART in rural Tanzania,” conclude the authors. “These results reinforce the current knowledge about the low sensitivity of the WHO criteria for immunological treatment failure in children and adolescents. These findings…raise concern about the effectiveness of current paediatric ART programmes in Sub-Saharan Africa, calling for a critical review of current guidance.”